Abstract

Epithelial ovarian cancer (EOC) represents the most frequent cause of death in the
United States from a cancer involving the female genital tract. Contributing to the
overall poor outcome in EOC patients, are the metastases to the peritoneum and stroma
that are common in this cancer. In one study, cDNA microarray analysis was performed
on fresh tissue to profile gene expression in patients with EOC. This study showed
a number of genes with significantly altered expression in the pelvic peritoneum and
stroma, and in the vicinity of EOC implants. These genes included those encoding coagulation
factors and regulatory proteins in the coagulation cascade and genes encoding proteins
associated with inflammatory responses. In addition to promoting the formation of
blood clots, coagulation factors exhibit many other biologic functions as well as
tumorigenic functions, the later including tumor cell proliferation, angiogenesis,
invasion, and metastasis. Coagulation pathway proteins involved in tumorigenesis consist
of factor II (thrombin), thrombin receptor (protease-activated receptors), factor
III (tissue factor), factor VII, factor X and factor I (fibrinogen), and fibrin and
factor XIII. In a recent study we conducted, we found that factor XII, factor XI,
and several coagulation regulatory proteins, including heparin cofactor-II and epithelial
protein C receptor (EPCR), were also upregulated in the peritoneum of EOC.

In this review, we summarize evidence in support of a role for these factors in promoting
tumor cell progression and the formation of ascites. We also discuss the different
roles of coagulation factor pathways in the tumor and peritumoral microenvironments
as they relate to angiogenesis, proliferation, invasion, and metastasis. . Since inflammatory
responses are another characteristic of the peritoneum in EOC, we also discuss the
linkage between the coagulation cascade and the cytokines/chemokines involved in inflammation.
Interleukin-8, which is considered an important chemokine associated with tumor progression,
appears to be a linkage point for coagulation and inflammation in malignancy. Lastly,
we review findings regarding the inflammatory process yielded by certain clinical
trials of agents that target members of the coagulation cascade in the treatment of
cancer. Current data suggest that disrupting certain elements of the coagulation and
inflammation processes in the tumor microenvironment could be a new biologic approach
to cancer therapeutics.